Prostate cancer is the second most common cause of cancer death among men in the United States. The first-line therapy for metastatic prostate cancer is suppression of testicular androgen synthesis. Testosterone precursors derived from the adrenal gland, the adrenal androgens, may contribute as much as 25% of the androgen load in the prostate, but there is no safe and effective drug which inhibits adrenal androgen production. The nuclear receptors, a rich source of new drug targets, control gene expression through interaction of small molecules with a conserved ligand-binding domain. The orphan nuclear receptor SF-1 (steroidogenic factor-I) regulates steroid hormone production and adrenal gland function and is mainly expressed in steroidogenic tissues. The goal of this project is to identify small molecule drugs that suppress adrenal androgen synthesis through SF-1. In the clinic, such a therapeutic drug could be combined with current testicular androgen suppression therapies to achieve total androgen suppression and significantly delay the appearance of the androgen independent form of prostate cancer. Key aims are to: (1) Optimize cell-based receptor gene activation and indirect binding assays for compound screening of SF-1; (2) screen targeted chemical libraries to identify structurally diverse hits; (3) identify more potent SF-1 ligands through focused chemical synthesis and (4) characterize SF-1 ligand regulation of steroid hormone synthesis in steroidogenic cell lines. In Phase II, antagonist ligands of high affinity and specificity will be synthesized that suppress adrenal androgens, and lead compounds developed for animal testing. Preclinical and clinical testing for commercialization will be carried out with a major partner in the pharmaceutical industry.